Gene expression during ER stress–induced apoptosis in neurons: induction of the BH3-only protein Bbc3/PUMA and activation of the mitochondrial apoptosis …

C Reimertz, D Kögel, A Rami, T Chittenden… - The Journal of cell …, 2003 - rupress.org
C Reimertz, D Kögel, A Rami, T Chittenden, JHM Prehn
The Journal of cell biology, 2003rupress.org
Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of ischemic and
neurodegenerative disorders. Treatment of human SH-SY5Y neuroblastoma cells with
tunicamycin, an inhibitor of protein glycosylation, rapidly induced the expression of target
genes of the unfolded protein response. However, prolonged treatment also triggered a
delayed, caspase-dependent cell death. Microarray analysis of gene expression changes
during tunicamycin-induced apoptosis revealed that the Bcl-2 homology domain 3-only …
Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of ischemic and neurodegenerative disorders. Treatment of human SH-SY5Y neuroblastoma cells with tunicamycin, an inhibitor of protein glycosylation, rapidly induced the expression of target genes of the unfolded protein response. However, prolonged treatment also triggered a delayed, caspase-dependent cell death. Microarray analysis of gene expression changes during tunicamycin-induced apoptosis revealed that the Bcl-2 homology domain 3-only family member, Bcl-2 binding component 3/p53 upregulated modulator of apoptosis (Bbc3/PUMA), was the most strongly induced pro-apoptotic gene. Expression of Bbc3/PUMA correlated with a Bcl-xL–sensitive release of cytochrome c and the activation of caspase-9 and -3. Increased expression of Bbc3/PUMA was also observed in p53-deficient human cells, in response to the ER stressor thapsigargin, and in rat hippocampal neurons after transient forebrain ischemia. Overexpression of Bbc3/PUMA was sufficient to trigger apoptosis in SH-SY5Y neuroblastoma cells, and human cells deficient in Bbc3/PUMA showed dramatically reduced apoptosis in response to ER stress. Our data suggest that the transcriptional induction of Bbc3/PUMA may be sufficient and necessary for ER stress–induced apoptosis.
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